Tetrazines protonation

The mass spectra of 1,2,4,5-tetrazines 1 are very simple. In most cases a fragmentation to one molecule of nitrogen and two molecules of the appropriate nitriles was observed.190,373 In dialkyl-1,2,4,5-tetrazines protonated and deprotonated nitrile structures were also observed.195 In the spectra of 3,6-diaryl-l,2,4,5-tetrazines peaks at a mass unit [M+ +2] were observed, which were explained by the formation of diaryldihydro-l,2,4,5-tetrazines in the ion source.372... 

Infrared and proton resonance spectra indicate that the tetrazine-dithione 223a exists in the dithione form shown. ... 

In 1971, two papers concerning the parent compound (4) appeared almost simultaneously. As was pointed out in Section III,A, Warrener found that 3,6-dipyridyl-l,2,4,5-tetrazine (64) reacts with 15 to give 66 a lack of coupling between the methine protons is consistent with the assigned stereochemistry. Compound 66 is quite stable in solution below — 20°C but slowly decomposes on storage in the solid state. It reacted with N-methylmaleimide to give Diels Alder adducts of 4 namely 79 and 80 (not isolated composition... 

Oxidation of (144) to give the pyridazine (146). For this reaction it is necessary that the alkene has protons at each end of the double bond. Very often an excess of the tetrazine acts as the oxidizing agent. 

No reports of reactions of simple tetrazines have been collected during the past year. However, studies of the protonation and acid stability of the fused ring tetrazine antitumour agent "Temozolomide" (76) have been carried out and the NMR spectra of a number of Temozolomide derivatives carrying NMR active nuclei (l3C, l5N) at different positions have been recorded (95JCS(P1)249],... 

Figure 5.7 Schematic representation of the energy levels of a tetrazine-bridged osmium poly-pyridyl monolayer in the protonated and deprotonated states...

The monocyclic diazines, triazines, and tetrazines are all theoretically subject to electrophilic attack at one or more of their annular nitrogen atoms by protons alkylating, acylating, and aminating reagents and peracids. Coordination with metals could also be classified under this heading. 

The direct determination of SA values for more acidic solvents was not possible because in such solvents the indicator dyes (52) and (53) are protonated at the carbonyl oxygen atom. For such acidic solvents, 3,6-diethyl-l,2,4,5-tetrazine (DETZ) was introduced as a third probe dye [337b]. This aromatic tetrazine exhibits a solvent-dependent n n absorption in the visible region a change from methylcyclohexane = 550 nm) to hexafluoro-2-propanol (Imax = 517 nm) leads to a hypsochromic band shift of A2 = —33 nm (Av = +1160 cm ), mainly due to the HBD acidity of the... 

A strong deshielding observed for protons and C-atoms situated between two heteroatoms is expected and observed for pyrimidine, 1,2,4-triazine, 1,3,5-triazine and 1,2,4,5-tetrazine, culminating for the H-NMR chemical shift of the latter compound. 

A number of aliphatic hydrazones (374) are slowly transformed into the solid hexahydro-1,2,4,5-tetrazines (375) when left at room temperature. Addition of acetic acid/acetate buffer (pH = 5.5) to the hydrazone causes almost instantaneous conversion of the hydrazone into the hexahydrotetrazine. This acceleration of the rate of dimerization suggests the intermediacy of a protonated hydrazone (376) (77TL3155, 73ACS779, 72TL949, 71AJC1859, 70TL2199,63 AG 1204). In acidic media there is an equilibrium between the hexahydrotetrazines and the hydrazones (70HCA251). The hydrazones (374) are also intermediates in the preparation of the hexahydrotetrazines from aldehydes and hydrazines. 

When l,8-bis(dimethylamino)-4-vinylnaphthalene (121) is heated with 3,6-diphenyl-s-tetrazine (DFT), a [4 + 2]-cycloaddition reaction with reverse electron demands takes place to give the 1,4-dihydropyridazine derivative 208 (Scheme 37). The latter could be oxidized with chloranil or with excess of DFT to pyridazine 209118. A similar reaction with acenaphthylene proton sponge 107 gives directly the annelated pyridazine 139, since the intermediate dihydropyridazine is readily oxidized in air. It was established that the reactivity ratio of compounds 107, 121, 5-dimethylaminoacenaphthylene and acenaphthylene in the reaction with DFT is equal to 32 17 14 1, respectively. These data are in... 

Phenylcyclopenta[e][l,2,3,4]tetrazine (1) undergoes electrophilic substitution reactions preferentially at C7, as has been demonstrated by bromination with A-bromosuccinimide, formy-lation with phosphoryl chloride/dimethyl formamide and trifluoroacetylation with trifluo-roacetic anhydride/triethylamine.37 Addition of tetrafluoroboric acid to 1 results in the formation of the protonated salt 2.37... 

The second (3 + 3) fragment method concerns reactions which can be explained as dimerization of nitrile imines 8. Since in most cases R2 is a substituent and not a proton, these reactions give 1,4-disubstituted 1,4-dihydro-l,2,4,5-tetrazines 9 which cannot be transformed into aromatic 1,2,4,5-tetrazines 10. These reactions will not be discussed in detail. 

Apparently, no alkylation, arylation, acylation or /V-amination of a heteroaromatic 1,2,4,5-tetrazine ring has been reported so far, but alkylation or acylation of substituents bound to the 1,2,4,5-tetrazine ring are known (see Section 5.1.4.6.). Treatment of 1,2,4,5-tetrazines with acids affords ring-opened products in the presence of water or alcohols a protonated 1,2,4,5-tetrazinium salt may be an intermediate in this reaction. 

Hartree-Fock calculations with the 6-3IG basis have been performed to investigate the structure and the Li binding energies of the complexes between Li and diazines, triazines, and tetrazines <90TCAi>. The correlations between calculated Li" binding energies and proton affinities are compared. 

A possible borderline case is observed in the reactions of tetrazines with cyclic ketene A,A-aminals (Scheme 51) <89AG(E)1267>. Hartmann and Heuschmann offered some evidence that the dipolar intermediate (199) isolable in their system might be a true intermediate in a two-step (4- -2) cycloaddition. There are a few examples <90TH 621-02,93UP 621-01 > which contradict their assumption. Tetrazine (166) and aminal (290) react to form the dipole (291), which can be protonated to (292) (NMR) but the cycloaddition forms (294), the product with we/a-orientation, via (293). 

---